Accelerated graft atherosclerosis, a manifestation of chronic rejection, is the leading cause of late graft failure in patients surviving the first year post transplantation. The development of antibodies to donor HLA antigens is a major risk factor associated with transplant atherosclerosis. The overal goal of this proposal is to determine the mechanism(s) through which anti-HLA antibodies stimulate endothelial cell (EC) and smooth muscle cell (SMC) activation and proliferation.
In specific aim 1, the investigators will establish whether exposure of endothelial cells to anti-HLA antibodies from patients with transplant atherosclerosis is accompanied by the production of growth factors. Donor EC will be treated with recipient anti-HLA antibodies and the production of basic fibroblast growth factor (bFGF) will be assessed. The ability of anti- HLA antibodies to upregulate growth factor ligand binding will be evaluated using bFGF radioligand binding assays. The investigators will also determine whether exposure of endothelial cells to anti-HLA antibodies leads to increased permeability of the EC monolayer and de novo expression of adhesion molecules. The interaction of anti-HLA antibodies with the endothelium in the presence of cytokines will be examined.
In specific aim 2, the investigators will determine whether anti-HLA antibodies stimulate the proliferation of primary cultures of donor SMC. These experiments will assess whether anti-HLA antibodies induce EC to secrete growth factors that stimulate proliferation of SMC and second whether anti-HLA antibodies bind to and stimulate SMC proliferation directly. The ability of inflammatory cytokines to augment proliferative effects of anti-HLA antibodies on SMC will be evaluated.
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